Review ArticleEvidence-based pharmacotherapy for prevention and management of cardiac allograft vasculopathy
Section snippets
Use of immunosuppressants
Immunosuppressants are an essential component of all transplant patients' regimens. They have been institutionalised for their anti-proliferative effects and prophylactic potential against acute allograft rejection. Given their antiproliferative activity, it is believed that drugs such as proliferation signalling inhibitors (sirolimus and everolimus) which inhibits mammalian target of rapamycin (mTOR) and limit proliferation of T-cells and smooth muscle cells, will be effective in preventing
Efficacy and mechanism of action
Prevention options for CAV to date remain limited. As discussed previously, development of CAV is both cholesterol dependent and independent, with dyslipidemia occurring in 60–80% of HT recipients.39 In fact, a retrospective cohort analysis in 2018 of 37 patients, found that 12 (32.4%) out of the 37 patients with low-density lipoprotein cholesterol (LDL-C) ≥100 mg/dl developed CAV, vs 25 (15.9%) out of the 157 patients with LDL-C <100 mg/dl (P = 0.021). Time to CAV was also delayed when a
Other pharmacological approaches
Besides the use of immunosuppressants and statins for the prevention of CAV, a plethora of other unconventional pharmacological approaches have been studied. Table 4 outlines the evidence for their use.
Pharmacological management of established CAV
Despite the plethora of studies on the potential therapies for CAV prophylaxis, the treatment and management of an established diagnosis of CAV remains limited. However, progress has been made with the use of augmented immunosuppressive therapies to attenuate CAV development.
A prospective study investigated the potential reversal of early vasculopathy with the use of 3-day methylprednisolone pulse (an anti-inflammatory corticosteroid) and ATG. Out of the 76 patients who were followed up for
Preclinical investigations
Basic science investigations are leading the way in the discovery of new therapies that may have a potential in combating and preventing CAV. Several studies on animal models have reached promising conclusions for the future of CAV. Table 5 below outlines the most prominent preclinical studies related to CAV prevention and management.
These studies introduce new possibilities for the future prevention and management of CAV. Although the findings may be predictive of translational outcomes with
Conclusion and expert opinion
Cardiac allograft vasculopathy is a troublesome long-term complication in HT recipients. Due to the limited available treatment options along with the poor allograft survival prognosis, prevention continues to be a cornerstone of CAV. Antiproliferative immunosuppressive therapy with MMF is associated with only a modest decrease in intimal thickening and plaque progression, yet has been demonstrated to prolong overall survival post-HT. Although studies that have substituted everolimus for
Declaration of competing interest
MRM is a consultant for Abbott (fees paid to Brigham and Women's Hospital), Portola, Bayer, Baim Institute for Clinical Research and Triple Gene; a trial steering committee member for Medtronic and Janssen; a scientific advisory board member for Leviticus, NupulseCV and FineHeart; and a DSMB member for Mesoblast. Other authors have no pertinent disclosures.
References (102)
- et al.
Allograft vasculopathy: the Achilles’ heel of heart transplantation
J Am Coll Cardiol
(2016) - et al.
Heterogeneity of cardiac allograft vasculopathy: clinical insights from coronary angioscopy
J Am Coll Cardiol
(1997) The scourge and enigmatic journey of cardiac allograft vasculopathy
J Heart Lung Transplant
(2017)- et al.
The effect of everolimus initiation and calcineurin inhibitor elimination on cardiac allograft vasculopathy in de novo recipients: one-year results of a Scandinavian randomized trial
Am J Transplant
(2015) - et al.
Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: three-year results from the randomized SCHEDULE study
Am J Transplant
(2016) - et al.
Thrombotic events with proliferation signal inhibitor–based immunosuppression in cardiac transplantation
J Heart Lung Transplant
(2019) - et al.
Attenuation of cardiac allograft vasculopathy by sirolimus: relationship to time interval after heart transplantation
J Heart Lung Transplant
(2013) - et al.
Long-term sirolimus for primary immunosuppression in heart transplant recipients
J Am Coll Cardiol
(2018) - et al.
Outcomes associated with mammalian target of rapamycin (mTOR) inhibitors in heart transplant recipients: a meta-analysis
Int J Cardiol
(2018) - et al.
Incidence of malignancies in patients treated with sirolimus following heart transplantation
J Am Coll Cardiol
(2019)
TOR inhibitors and cardiac allograft vasculopathy: is inhibition of intimal thickening an adequate surrogate of benefit?
J Heart Lung Transplant
Preventing cardiac allograft vasculopathy: long-term beneficial effects of mycophenolate mofetil
J Heart Lung Transplant
De novo sirolimus with low-dose tacrolimus versus full-dose tacrolimus with mycophenolate mofetil after heart transplantation—8-year results
J Heart Lung Transplant
Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients
Am J Transplant
Accelerated allograft vasculopathy with rituximab after cardiac transplantation
J Am Coll Cardiol
Use of anti-thymocyte globulin for induction therapy in cardiac transplantation: a review
Delayed onset of cardiac allograft vasculopathy by induction therapy using anti-thymocyte globulin
J Heart Lung Transplant
Ten-year follow-up of a prospective, randomized trial of BT563/bb10 versus anti-thymocyte globulin as induction therapy after heart transplantation
J Heart Lung Transplant
Reduction of alloantibodies via proteasome inhibition in cardiac transplantation
J Heart Lung Transplant
Statin therapy in cardiac allograft vasculopathy progression in heart transplant patients: does potency matter?
Transplant Rev
Safety and efficacy of rosuvastatin therapy for the prevention of hyperlipidemia in adult cardiac transplant recipients
J Heart Lung Transplant
Metaanalysis of statins and survival in de novo cardiac transplantation
A clinician’s guide to statin drug-drug interactions
J Clin Lipidol
Statin safety and drug interactions: clinical implications
Am J Cardiol
Comparative beneficial effects of simvastatin and pravastatin on cardiac allograft rejection and survival
J Am Coll Cardiol
Safety and tolerability of high intensity statin therapy in heart transplant patients receiving immunosuppression with tacrolimus
J Heart Lung Transplant
Intensity of statin therapy affects progression of coronary artery vasculopathy
J Heart Lung Transplant
Higher intensity statin therapy reduces clinical endpoints after heart transplantation independent of lipid levels
J Heart Lung Transplant
Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation
J Heart Lung Transplant
Statin therapy is not associated with improved outcomes after heart transplantation in children and adolescents
J Heart Lung Transplant
Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial
Lancet
The use of vitamin C and E after heart transplant revisited
J Am Coll Cardiol
Early vitamin C and E supplementation and cardiac allograft vasculopathy: 10-year follow-up from a randomized, controlled study
J Heart Lung Transplant
Early aspirin use and the development of cardiac allograft vasculopathy
J Heart Lung Transplant
Angiotensin-converting enzyme inhibition early after heart transplantation
J Am Coll Cardiol
The effect of combined angiotensin-converting enzyme inhibition and calcium antagonism on allograft coronary vasculopathy validated by intravascular ultrasound
J Heart Lung Transplant
Prophylaxis versus preemptive anti-cytomegalovirus approach for prevention of allograft vasculopathy in heart transplant recipients
J Heart Lung Transplant
Homocysteine-lowering therapy and early progression of transplant vasculopathy: a prospective, randomized, IVUS-based study
Am J Transplant
Immunologic response to PCSK9 inhibitors in orthotopic heart transplant recipients: a case series
J Card Fail
Lipid-lowering therapy and long-term survival in heart transplantation
Am J Cardiol
Management of dyslipidemia in adult solid organ transplant recipients
J Clin Lipidol
Granulocyte colony-stimulating factor therapy is associated with a reduced incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients
Efficacy of augmented immunosuppressive therapy for early vasculopathy in heart transplantation
J Am Coll Cardiol
398: premature termination of a prospective, open label, randomized, multicenter study of sirolimus to replace calcineurin inhibitors (CNI) in a standard care regimen of CNI, MMF and corticosteroids early after heart transplantation
J Heart Lung Transplant
Effects of different serotonin receptor subtype antagonists on the development of cardiac allograft vasculopathy in murine aortic allografts
Transpl Immunol
Long-term outcome following heart transplantation: current perspective. Journal of Thoracic Disease, [online] 7(3), p.549
International thoracic organ transplant (TTX) registry data slides
Cardiac allograft vasculopathy: an ongoing challenge in the care of heart transplant recipients
Cardiac Transplant
Recent advances in allograft vasculopathy
Curr Opin Organ Transplant
Cardiac allograft vasculopathy: a review
Catheter Cardiovasc Interv
Cited by (13)
Long-term efficacy of everolimus as de novo immunosuppressant on the cardiac allograft vasculopathy in heart transplant recipients
2022, AtherosclerosisCitation Excerpt :Moreover, mammalian target of rapamycin (mTOR) inhibitors are immunosuppressants that exert antiproliferative effects on fibroblasts and smooth muscle cells. As a result, they have the potential to reduce intimal hyperplasia in the coronary arteries, thereby preventing CAV progression [3]. The use of mTOR inhibitors in place of azathioprine or mycophenolate mofetil (MMF) as secondary immunosuppressive agents and in combination with lower doses of calcineurin inhibitors (CNIs) attenuated the progression of CAV [4–6].
Ferroptosis and its role in cardiomyopathy
2022, Biomedicine and PharmacotherapyCitation Excerpt :Endothelial cell dysfunction caused by allograft injury is the main reason of CAV. The injury affects all parts of the cardiac vascular tree, causes inner intimal and plaque progression, and the treatment is still limited now [168]. Ferroptosis is significantly associate with endothelial cell dysfunction [169,170].
Progress in Cardiovascular Diseases Statistics 2022
2022, Progress in Cardiovascular DiseasesCardiac allograft vasculopathy in transplanted hearts: Perspectives on the disease and revascularization options
2022, Debulking in Cardiovascular Interventions and Revascularization Strategies: Between a Rock and the HeartNine Years as Editor-in Chief of Progress in Cardiovascular Diseases
2022, Progress in Cardiovascular DiseasesSpecial Assorted Topics 2021
2021, Progress in Cardiovascular Diseases